PGC-1α Acetylation Research Articles

PGC-1α Serine 570 Phosphorylation and GCN5-mediated Acetylation by Angiotensin II Drive Catalase Down-regulation and Vascular Hypertrophy

Angiotensin II (Ang II) is a pleuripotential hormone that is important in the pathophysiology of multiple conditions including aging, cardiovascular and renal diseases, and insulin resistance. Reactive oxygen species (ROS) are important mediators of Ang II-induced signaling generally and have a well defined role in vascular hypertrophy, which is inhibited by overexpression of catalase, inferring a specific role of H(2)O(2). The molecular mechanisms are understood incompletely. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a key regulator of energy metabolism and ROS-scavenging enzymes including catalase. We show that Ang II stimulates Akt-dependent PGC-1 alpha serine 570 phosphorylation, which is required for the binding of the histone acetyltransferase GCN5 (general control nonderepressible 5) to PGC-1 alpha and for its lysine acetylation. These sequential post-translational modifications suppress PGC-1 alpha activity and prevent its binding to the catalase promoter through the forkhead box O1 transcription factor, thus decreasing catalase expression. We demonstrate that overexpression of the phosphorylation-defective mutant PGC-1 alpha (S570A) prevents Ang II-induced increases in H(2)O(2) levels and hypertrophy ([(3)H]leucine incorporation). Knockdown of PGC-1 alpha by small interfering RNA promotes basal and Ang II-stimulated ROS and hypertrophy, which is reversed by polyethylene glycol-conjugated catalase. Thus, endogenous PGC-1 alpha is a negative regulator of vascular hypertrophy by up-regulating catalase expression and thus reducing ROS levels. We provide novel mechanistic insights by which Ang II may mediate its ROS-dependent pathophysiologic effects on multiple cardiometabolic diseases.

The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α

Transcriptional control of metabolic circuits requires coordination between specific transcription factors and coregulators and is often deregulated in metabolic diseases. We characterized here the mechanisms through which the coactivator SRC-3 controls energy homeostasis. SRC-3 knock-out mice present a more favorable metabolic profile relative to their wild-type littermates. This metabolic improvement in SRC-3(-/-) mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1alpha. By controlling the expression of the only characterized PGC-1alpha acetyltransferase GCN5, SRC-3 induces PGC-1alpha acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1alpha activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1alpha activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1alpha as an effector to control mitochondrial function and energy homeostasis.

Nutrient Sensing Through Metabolic Transcription‐Dependent Acetylation

Fluctuations in nutrients are sensed in cells and trigger a metabolic adaptive response to ensure homeostasis for energy and nutrients. For example, nutrient deprivation increases genes involved in mitochondrial fatty acid oxidation and glucose production. A key control occurs at the transcriptional level and coordinates the expression of metabolic genes. Among the major components of this transcriptional circuitry are the PGC‐1α transcriptional coactivator complexes. Using skeletal muscle cells as a metabolic model system we found a nutrient sensing pathway that control fatty acid mitochondrial oxidative function. This pathway involves a response to low nutrients and glucose that in a cell‐autonomous manner switches from glucose to fatty acid oxidation via an increase in a specific subset of mitochondrial genes. This coordination switch to fatty acid oxidation and full respiration activities is controlled through a mechanism of low glucose stimulated SIRT1‐dependent deacetylation and activation of PGC‐1α. De‐acetylated PGC‐1α is bound to promoters and activates genes involved in oxidation of fatty acids. In this regard, SIRT1 deficient cells lack the ability to undergo this nutrient switch under low glucose concentrations. Conversely, in high glucose concentrations PGC‐1α is acetylated through the GCN5 Acetyl Transferase Complex, leading to decreases in mitochondrial fatty acid oxidation. Mechanistically, acetylation of PGC‐1α results in inactivation of the transcriptional activity and displacement from the active chromatin to a different subnuclear localization. In summary, we have identified a nutrient‐dependent molecular mechanisms that involve regulation of PGC‐1α and mediate control of skeletal muscle mitochondrial nutrient oxidation activities.

Fat But Healthy

Resveratrol is a polyphenolic compound produced by plants and found in red wine. It has been reported to extend life span in various model organisms, presumably through its ability to stimulate the deacetylase activity of sirtuins (there are seven isoforms in mammals, SIRT1 through 7). Baur et al . report that in mice, the addition of resveratrol to a high-calorie, high-fat diet (HCR) prevented much of the aging and disease associated with obesity without affecting body weight. Mice fed the HCR diet showed increased life span compared with high-calorie, high-fat diet (HC)-fed mice, and longevity was similar to that of mice on a standard diet. HCR mice exhibited greater insulin sensitivity and decreased circulating concentrations of glucose, insulin, and insulin-like growth factor 1 (IGF-1). The activity of adenosine monophosphate-activated protein kinase (AMPK), which is a crucial regulator of metabolism, was increased to a greater extent in the livers of the HCR-fed mice than in the livers of the HC-fed mice. Histology and assessment of various markers for the function of liver, pancreas, and heart indicated that the HCR diet prevented the damage associated with obesity. Acetylation of PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) was decreased in the livers of the HCR-fed mice. PGC-1α is a substrate for SIRT1, and its acetylation status is used as a measure of SIRT activity. Parametric analysis of gene set enrichment (PAGE), a computational method for analyzing microarray data, suggested that resveratrol affected 127 biochemical and signaling pathways. Notable were the down-regulation of genes associated with insulin signaling and metabolism and the up-regulation of genes associated with STAT3 (signal transducer and activator of transcription 3) signaling. STAT3 signaling declines with age and may contribute to liver regeneration. Although it would obviously be best to limit caloric intake and exercise, this study suggests that there may be pharmacological interventions that can prevent some of the diseases associated with obesity (see Kaeberlein and Rabinovitch). M. Kaeberlein, P. S. Rabinovitch, Grapes versus gluttony. Nature 444 , 280-281 (2006). [PubMed] J. A. Baur, K. J. Pearson, N. L. Price, H. A. Jamieson, C. Lerin, A. Kalra, V. V. Prabhu, J. S. Allard, G. Lopez-Lluch, K. Lewis, P. J. Pistell, S. Poosala, K. G. Becker, O. Boss, D. Gwinn, M. Wang, S. Ramaswamy, K. W. Fishbein, R. G. Spencer, E. G. Lakatta, D. Le Couteur, R. J. Shaw, P. Navas, P. Puigserver, D. K. Ingram, R. de Cabo, D. A. Sinclair, Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444 , 337-342 (2006). [PubMed]